Field of the Invention
The present invention relates to cross-metathesis of polysaccharides with one or more olefin-terminated side chains and cross-metathesized products thereof.
Description of Related Art
Modified polysaccharides are extremely important materials for purposes as diverse as drug delivery, adhesive tape, automobile coatings, house paint, and flat screen displays (Edgar, K. J.; Buchanan, C. M.; Debenham, J. S.; Rundquist, P. A.; Seiler, B. D.; Shelton, M. C.; Tindall. D, Advances in cellulose ester performance and application. Prog. Polym. Sci. 2001, 26, 1605-1688). Even so, modern polymer science has had little impact on increasing the variety of commercial polysaccharide derivatives available to meet current demanding materials needs. Cellulose derivatives are the most commercially important polysaccharide-based materials; nearly the entire cellulose derivative market involves derivatives with substituents selected from among just five ether types (methyl, ethyl, carboxymethyl, hydroxyethyl, and hydroxypropyl) and five ester types (acetate, propionate, butyrate, succinate, and phthalate). Furthermore, synthesis of these derivatives requires the use of somewhat forcing conditions; strong acid catalysts like sulfuric acid in the case of cellulose ester synthesis, and strong base catalysts like sodium hydroxide in the case of cellulose ether synthesis, for example. Such conditions are not conducive to reaction of the polysaccharide with sensitive moieties. The remarkable recent achievements in polymer chemistry have not been successfully applied to polysaccharides to create useful new derivatives that can be practically prepared. In order to successfully meet these demanding application needs, and to create a renewable-based economy, we must succeed in creating efficient pathways to a more diverse set of renewable polysaccharide-based materials.
Olefin metathesis has been developed in recent years as a powerful, versatile tool for the synthesis of complex small molecules, as well as the polymerization of olefinic monomers to create novel and useful polymeric structures. In olefin metathesis, metal carbene complexes are used to rearrange double bonds in carbon skeletons with high functional group tolerance and under mild reaction conditions. Although ring closing metathesis (RCM) and ring opening metathesis polymerization (ROMP) have been comprehensively investigated over the past decade, olefin cross-metathesis (CM) has become an increasingly powerful tool in both organic and polymer chemistry thanks to the publication of Grubbs' model of selectivity for CMI and the development of active and selective CM catalysts (Samojlowicz, C.; Bieniek, M.; Grela, K., Ruthenium-Based Olefin Metathesis Catalysts Bearing N-Heterocyclic Carbene Ligands. Chem. Rev. 2009, 109, (8), 3708-3742; and Vougioukalakis, G. C.; Grubbs, R. H., Synthesis and Activity of Ruthenium Olefin Metathesis Catalysts Coordinated with Thiazol-2-ylidene Ligands. J. Am. Chem. Soc. 2008, 130, (7), 2234-2245).
It is instructive that these valuable new tools have not yet been exploited for synthesis of a wide variety of new polysaccharide derivatives. Only a few related studies have appeared; one example is the work by Reddy and co-workers (Reddy, C. R.; Jithender, E.; Prasad, K. R., Total Syntheses of the Proposed Structure for Ieodoglucomides A and B. J. Org. Chem. 2013, 78, (9), 4251-4260) who successfully cross-metathesized glucose-linked olefins with amino acid-appended olefins to construct the complete carbon skeleton of ieodoglucomides A and B, two unique glycopeptides isolated from marine-derived bacteria. What about similar CM reactions between, for example, a cellulose derivative bearing unsaturated side chains, and other olefin species, which could lead to a rich variety of otherwise inaccessible derivatives? Surprisingly, only a handful of studies have described metathesis reactions of polysaccharide derivatives, and none of them have described successful CM. In a typical example, Joly et al. observed self-metathesis (SM) of cellulose 10 undecenoate using Grubbs' catalyst (1st generation), affording crosslinked and insoluble cellulose plastic films (Joly, N.; Granet, R.; Krausz, P., Olefin Metathesis Applied to Cellulose Derivatives—Synthesis, Analysis, and Properties of New Crosslinked Cellulose Plastic Films. Journal of Polymer Science Part a—Polym. Chem. 2005, 43, (2), 407-418). All such studies to date have reported dominant self-metathesis of olefin substituted polysaccharides to afford crosslinked, insoluble products. This is not surprising; metathesis of polysaccharide derivatives containing pendent olefin groups (especially reactive Type 1 olefins by Grubbs' classification) must be nearly perfectly selective for cross-metathesis rather than self-metathesis in order to avoid cross-linking that would render the polymer insoluble, difficult to melt-process, and overall very difficult to process into desired shapes. Perhaps it is the negative results of these studies that have discouraged further investigation of cross-metathesis in polysaccharide derivatives.
In order to obtain discrete, soluble, polysaccharide-olefin CM products, SM between pendant terminal olefins must be absent, and there must be a high degree of conversion to CM products. Previous studies in other systems have shown that the type of catalyst (shown in FIGS. 1A-C) used influences the ability to obtain a high degree of conversion to cross-metathesis products. The Grubbs' 1st generation catalyst (FIG. 1A) has proved to be insufficiently effective as a cross-metathesis catalyst in all but simple reactions (Rybak, A.; Meier, M. A. R., Cross-metathesis of Fatty Acid Derivatives with Methyl Acrylate: Renewable Raw Materials for the Chemical Industry. Green Chem. 2007, 9, (12), 1356-1361; and Bruneau, C.; Fischmeister, C.; Miao, X.; Malacea, R.; Dixneuf, P. H., Cross-metathesis with acrylonitrile and applications to fatty acid derivatives. Eur. J. Lipid Sci. Tech. 2010, 112, (1), 3-9).
More reactive and thermally stable Grubbs' 2nd generation (FIG. 1B) and Hoveyda-Grubbs' 2nd generation (FIG. 1C) catalysts have been heavily studied for CM reactions. Compared with Grubbs' 2nd generation, the Hoveyda-Grubbs catalyst (FIG. 1C) is more reactive towards electron-deficient olefins, and it can initiate metathesis at lower temperature. While the degree of conversion depends on the catalyst used, selectivity in CM is dependent primarily upon the structure of the reacting olefin. Based on chemical structure and reactivity results, Grubbs empirically classified olefins into 4 types (shown in Table 1) (Chatterjee, A. K.; Choi, T. L.; Sanders, D. P.; Grubbs, R. H., A General Model for Selectivity in Olefin Cross Metathesis. J. Am. Chem. Soc. 2003, 12S, (37), 11360-11370).
TABLE 1Grubbs' Categorization of Olefins and Rules for SelectivityOlefinTypeOlefin Metathesis ReactivityExamplesaType IRapid homodimerization,terminal olefinshomodimer consumableType IISlow homodimerization, homodimeracrylates, acrylic acids,sparingly consumableacrylamidesType IIINo homodimerizationallylic alcohol (protected)Type IVOlefins inert to CM, but dovinyl nitro olefinsnot deactivate the catalyst (Spectator)aSelectivity depends on catalyst used. The examples shown are valid for Grubbs' 2nd generation catalyst.Grubbs' Rules:Reactions between two olefins of Type I = Statistical SM and CMReactions between two olefins of same type (non-Type 1) = Non-selective CMReactions between two different types (except Type IV) = Selective CM
Sterically-hindered and electron-deficient olefins of type II and III have low metathesis reactivity and only slowly homodimerize, while more reactive terminal olefins (type I) readily undergo homodimerization via metathesis. Moreover, the homodimers of the terminal olefins are susceptible to subsequent secondary CM reactions. As a result, when a type I olefin is reacted with a type II or III olefin, high conversion to a CM product can be achieved by employing an excess of the type II or III olefin (Choi, T. L.; Chatterjee, A, K.; Grubbs, R. H., Synthesis of α,β-Unsaturated Amides by Olefin Crossmetathesis. Angew. Chem. Int. Ed. 2001, 40, (7), 1277).
The synthesis of cellulose derivatives containing carboxyl groups has been a long-standing and fascinating challenge. One issue is the problem of synthesizing derivatives with pendant carboxyl groups attached to a polysaccharide which also contains pendant hydroxyl groups; carrying out such a transformation under the acidic conditions commonly used to manufacture cellulose esters is almost inevitably accompanied by crosslinking due to ester formation between chains. This restricts such nucleophilic substitution chemistry to near-neutral or alkaline conditions, which work well for simple cases like reaction of cellulose with succinic anhydride (Li, W. Y.; Jin, A. X.; Liu, C. F.; Sun, R. C.; Zhang, A. P.; Kennedy, J. F., Homogeneous Modification of Cellulose with Succinic Anhydride in Ionic Liquid Using 4-Dimethylaminopyridine as A Catalyst. Carbohydr. Polym. 2009, 78, (3), 389-395) or adipic anhydride (Liu, H.; Kar, N.; Edgar, K., Direct Synthesis of Cellulose Adipate Derivatives Using Adipic Anhydride. Cellulose 2012, 19, (4), 1279-1293). Attachment of co-carboxyalkanoates in which the intervening polymethylene chain is too long for facile cyclic anhydride formation is more complicated; in the past, it has been necessary to resort to protection/deprotection methodologies (Liu, H.; Ilevbare, G. A.; Cherniawski, B. P.; Ritchie, E. T.; Taylor, L. S.; Edgar, K. J., Synthesis and Structure-Property Evaluation of Cellulose ω-Carboxyesters for Amorphous Solid Dispersions. Carbohydr. Polym., (2012), http://dx.doi.org/10.1016/j.carbpoJ.2012.11.049). Such difficulties are unfortunate since polysaccharide ω-carboxyalkanoates have many useful properties that enable important applications. In coating applications, the carboxylic acid functionality renders the derivatives water-soluble or water-dispersible, enabling waterborne and high solids coatings systems, thereby reducing the use of volatile organic solvents and enhancing coatings performance (Edgar, K. J.; Buchanan, C. M.; Debenham, J. S.; Rundquist, P. A.; Seiler. B. D.; Shelton, M. C.; Tindall, D., Advances in Cellulose Ester Performance and Application. Prog. Polym. Sci. 2001, 26, (9), 1605-1688). Cellulose derivatives containing carboxyl groups are also important components of drug delivery systems (Edgar, K. J., Cellulose Esters in Drug Delivery. Cellulose 2007, 14, (1),49-64). Since carboxylic acids have pKa values in the range of 4-5. carboxyl-containing polysaccharides are protonated in the strongly acidic environment of the stomach, and are ionized in the near-neutral small intestinal milieu. This pH-sensitivity makes the derivatives good candidates for enteric polymeric coatings or matrices, which minimize drug/stomach exposure by preventing release until the formulation reaches the higher pH environment of the small intestine. Cellulose acetate phthalate (CAPhth) was one of the first polymers used for such pH-sensitive, controlled release coatings in drug delivery (Merkle, H. P.; Speiser, P., Preparation and in Vitro Evaluation of Cellulose Acetate Phthalate Coacervate Microcapsules. J. Pharm. Sci. 1973, 62, (9), 1444-8). Other esters of cellulose with pendant carboxylic acid groups including cellulose acetate succinate (CAS) (Wilken, L. O., Jr.; Kochhar, M. M.; Bennett, D. P.; Cosgrove, F. P., Cellulose Acetate Succinate as an Enteric Coating for Some Compressed Tablets. J. Pharm. Sci. 1962, SI, 484-90), hydroxypropyl methylcellulose phthalate (HPMCP) (Kim, I. H.; Park, J. H.; Cheong, I. W.; Kim, J. H., Swelling and Drug Release Behavior of Tablets Coated with Aqueous Hydroxypropyl Methylcellulose Phthalate (HPMCP) Nanoparticles. J. Control. Release 2003, 89, (2), 225-233) and hydroxypropyl methylcellulose acetate succinate (HPMCAS) have also proven interesting for enteric coating and controlled release.
Recent studies have shown the advantages of esters of cellulose with pendant carboxylic acids in delivery of poorly soluble compounds (Biopharmaceutical Classification System (BCS) Class II), by forming miscible blends of polymers and drugs, termed amorphous solid dispersions (ASDs). These molecularly dispersed drugs generate higher solution concentrations than achievable from the corresponding crystalline drugs, by maximizing drug surface area and eliminating the need for the drug to overcome its heat of fusion in order to dissolve. Supersaturated drug solutions generated from these ASDs can not only enhance the absorption of the drug from the gastrointestinal (GI) tract, but also provide a pH-controlled release profile. For example, HPMCAS has been proven to be an effective polymer for initiating and maintaining drug supersaturation in the GI tract, stabilizing the amorphous drug against crystallization, thereby in some cases enhancing drug bioavailability (Curatolo, W.; Nightingale, J. A.; Herbig, S. M., Utility of Hydroxypropylmethyicellulose Acetate Succinate (HPMCAS) for Initiation and Maintenance of Drug Supersaturation in the GI Milieu. Pharm. Res. 2009, 26, (6), 1419-1431; and Konno, H.; Taylor, L. S., Influence of Different Polymers on the Crystallization Tendency of Molecularly Dispersed Amorphous Felodipine. J. Pharm. Sci. 2006, 95, (12), 2692-2705; B S Tanno, F.; Nishiyama, Y.; Kokubo, H.; Obara, S., Evaluation of Hypromellose Acetate Suctinate (HPMCAS) as a Carrier in Solid Dispersions. Drug Dev. Ind. Pharm. 2004, 30, (1), 9-17). More recently, the formation of ASDs of poorly water-soluble drugs and long-chain cellulose ω-carboxyalkanoates, i.e. cellulose adipate, suberate and sebacate derivatives, was investigated, and it was found that some of these polymers were highly effective at generating and maintaining supersaturated drug solutions by inhibiting nucleation and subsequent crystal growth (Ilevbare, G. A.; Liu, H.; Edgar, K. J.; Taylor, L. S., Understanding Polymer Properties Important for Crystal Growth Inhibition-Impact of Chemically Diverse Polymers on Solution Crystal Growth of Ritonavir. Cryst. Growth Des. 2012, 12, (6), 3133-3143; and Ilevbare, G. A.; Liu, H.; Edgar, K. J.; Taylor, L. S., Effect of Binary Additive Combinations on Solution Crystal Growth of the Poorly Water-Soluble Drug, Ritonavir. Cryst. Growth Des. 2012, 12, (12), 6050-6060; and Ilevbare, G. A.; Liu, H.; Edgar, K. J.; Taylor, L. S., Impact of Polymers on Crystal Growth Rate of Structurally Diverse Compounds from Aqueous Solution. Mol. Pharm. 2013, 10, (6), 2381-2393; and Ilevbare, G. A.; Liu, H.; Edgar, K. J.; Taylor, L. S., Maintaining Supersaturation in Aqueous Drug Solutions: Impact of Different Polymers on Induction Times. Cryst. Growth Des. 2013, 13, (2), 740-751). These studies also revealed that the DS of carboxylic acid functionality and the polymer hydrophobicity were key factors influencing the performance of the ASDs. The long side chains enhance the interactions of the polymers with hydrophobic drugs, while the pendant carboxylic acids provide both specific polymer-drug interactions and the pH-trigger for drug release through swelling of the ionized polymer matrix.
Thus, despite these investigations there remains a need in the art for advances in the synthesis of polysaccharide derivatives.